ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 256 of the NR2E3 protein (p.Ala256Glu). This variant is present in population databases (rs377257254, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive NR2E3-related conditions (PMID: 12963616, 25079116). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438229). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NR2E3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 25703721, 28300834). For these reasons, this variant has been classified as Pathogenic.

The NR2E3 c.767C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.

The p.Ala256Glu variant in NR2E3 has been reported in the compound heterozygous state 6 individuals with retinal disease (Sharon 2003 PMID:12963616, Hull 2014 PMID:25079116, Carss 2017 PMID: 28041643, Bryant 2018 PMID: 29343940). It has also been identified in 0.009% (3/34014) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID:438229). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Kanda 2009 PMID: 19898638, von Alpen 2015 PMID: 25703721). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Moderate, PP3.

The p.Ala256Glu variant in NR2E3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Identified in patients with features of an NR2E3-related retinal dystrophy in published literature (PMID: 25079116, 28041643, 15459973, 12963616); Published functional studies demonstrate impairment of protein localization, binding, and function (PMID: 19898638, 28300834); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19718767, 25703721, 25097241, 28300834, 15453866, 28041643, 15459973, 29343940, 12963616, 24425859, 16225923, 32679203, 31589614, Vafaeie[preprint], 38219857, 37510230, 32037395, 36460718, 31964843, 33513943, 25079116, 34906470, 19898638)